1. Field of the Invention
The present invention relates to a viral particle bearing immunogens and having immunopotentiation or adjuvant activity. The invention particularly relates to recombinant viral particles and method for enhancing an immune response in a human or an animal by means of these particles.
2. Description of Prior Art
Vaccination is the most efficient method to fight against infectious diseases. The appearance of new viral diseases (e.g. Hepatitis C virus, Human immunodeficiency virus), and the resistance of pathogenic bacteria (Salmonella typhii) to antibiotics are alarming. Vaccination thus become an efficient alternative to help controlling these diseases.
Over the last past 15 years, genetic engineering allowed the precise identification of protein fragments that are responsible for the protective immune response. Therefore, new vaccination strategies emerged. Immunisation of animals with appropriate immunogenic peptides allowed the production of neutralising antibodies that can control diseases. The expression of those immunogenic peptides in heterologous systems provided the basis of subunit vaccines.
Although it has been demonstrated that chemically synthesised oligopeptides are capable of stimulating the production of antibodies against the protein from which they are derived, the peptides themselves have generally been found to be insufficiently immunogenic to serve as vaccines. This is why there has been considerable interest in developing epitope-presentation systems, in which the peptide sequence is fused to a carrier molecule capable of assembly into a macromolecular structure.
Specific immunity can be enhanced by the use of immunopotentiators, such as adjuvants, when administering an antigen to a host. The immune response is mediated by a variety of cells in the immune system. There are two types of immune response: humoral immunity mediated by antibodies, and cellular immunity mediated primarily by cytotoxic T lymphocytes. Antigen presenting cells (“APC”) process and present antigen to both B and T cells. B cells secrete specific antibodies as a result of activation and T cells either become helper cells to the humoral response or cytotoxic cells and directly attack the antigen. Adjuvants have been shown to augment these immune responses.
Initial presentation of an antigen induces both IgM and IgG antibodies, forming the primary response. This production of antibodies may fall off, however, over time. A secondary response, which principally involves the production of IgG antibodies, may be triggered by the secondary or later in time presentation of the antigen. A secondary or even primary response, however, is not guaranteed merely by priming the host with an antigen.
A difficulty often encountered in the administration of an antigen is the extent to which the immune system will respond. Certain antigens are not very immunogenic in that upon administration they provoke a weak primary response or no response at all. In such cases, the immune system may not respond to a secondary challenge, and for example, the host may suffer from the disease or condition that the immunization with the antigen was designed to prevent.
In such situations, it is common to give a physiological response modulator (“PRM”). A PRM generally is defined as an immunopotentiating compound. It may be derived from bacteria, such as Bordella pertussis or Corynebacterium parvum. PRM also may include chemicals, such as polynucleotides, physiologically active molecules, such as thymic hormones, and adjuvants.
Adjuvants are compounds which enhance the immune systems response when administered with antigen producing higher antibody titres and prolonged host response. Commonly used adjuvants include Incomplete Freund's Adjuvant, which consists of a water in oil emulsion, Freund's Complete Adjuvant, which comprises the above with the addition of Mycobacterium tuberculosis, and alum. The difficulty, however, in using these materials in humans, for example, is that they are toxic or may cause the host to develop lesions at the site of injection.
Another approach was described by Kawamura and Berzofsky in J. Immunol., 136:58 (1986). In this approach, anti-Ig antibodies, which are reactive with immunoglobulins present on certain B cells, were conjugated to ferritin and myoglobin, and were administered to mice with Incomplete Freund's Adjuvant. Immunogenicity of the mixture was improved, but there was no indication of the immunogenicity of the mixture without the addition of the adjuvant. Also, whilst adjuvants such as Freund's complete adjuvant, Freund's Incomplete adjuvant and Montanide can greatly enhance the immune response to an antigen, they suffer from some disadvantages. When used with an antigen in an injectable form, large lesions often form at the site of injection, a situation which renders them unsatisfactory for such use in humans, pets or in meat animals. Furthermore, these adjuvants fail to act as immunopotentiating agents when administered orally or enterally.
It is know in the art that carriers of immunogen or antigens of different nature can be relatively easily genetically engineered. Plant virus are those systems that can be produced in plants and are easily adapted to this application. Cowpea mosaic virus (CPMV), tobacco mosaic virus X (TMVX), and alfalfa mosaic virus (AIMV) are known to having been modified for the presentation of epitopes of interest. Another plant viral vector, potato virus X (PVX), a member of the potexvirus group, is known to tolerate carriage of a complete protein overcoat. Also, U.S. Pat. Nos. 6,232,099 and 6,042,832, International Patent applications published under number WO 97/39134, WO 02/04007, WO 01/66778, WO 02/00169, and EP application 1167530, all describe different variations of virus-like particles carrying foreign proteins in fusion with endogenous proteins. However, nowhere in these references it is mentioned that such particles have any immunopotentiation or adjuvant properties.
Considering the state of the art described herein, there is still a great need for compounds and carrier particles allowing a strong immunization of human and animals while avoiding the use of adjuvants and second vaccinations as actually practiced.